Colorectal carcinoma (CRC) is the third leading cause of cancer morbidity and mortality in the United States. Familial Adenomatous Polyposis (FAP) represents one of the most common syndromes associated with high penetrant hereditary CRC. A prominent feature of cancer cells is their increased glucose uptake and reliance on aerobic glycolytic metabolism, a phenomenon described by Otto Warburg decades ago. Though it is a potential candidate for targeting against tumors, little is known about the mechanisms controlling it. Remarkably, we have recently identified the SIRT6 histone deacetylase as a central regulator of glycolytic metabolism: cells lacking SIRT6 undergo a dramatic metabolic switch, increasing lactate production while reducing mitochondrial respiration (Mostoslavsky et al., 2006; Zhong et al., 2010). In this proposal, we will study the role of SIRT6 in colorectal cancer cells. We hypothesize that colon cancer cells might selectively down-modulate SIRT6 to aquire a selective advantage in order to grow under conditions of aerobic glycolytic metabolism. Indeed, our preliminary results indicate that loss of SIRT6 provides tumorigenic potential to otherwise normal cells, modulating glycolysis and by- passing classical oncogenic pathways. Furthermore, SIRT6 levels are reduced in human tumors, predominantly in colon cancers. In this proposal, we will determine the precise role for SIRT6 in controlling glucose metabolism and the Warburg effect in the context of APC-dependent colorectal cancers. Specifically, we will 1) Study the role of SIRT6 in controlling the switch to glycolytic metabolism in colorectal cancer cells 2) Evaluate the role of SIRT6 in colon cancer in vivo using a conditional allele of SIRT6 in the context of a murine model of colorectal cancer 3) Determine the role of SIRT6 during the early events of APC-mediated cellular transformation using intestinal organoids derived from human FAP-specific induced-pluripotent stem (iPS) cells. Overall, our results should provide new insights into the molecular mechanisms regulating colon cancer metabolism. In this context, modulation of SIRT6 activity could provide us in the future with a potential therapeutic approach to tackle cancer development.